Normally when cardiac output falls, systemic vascular resistance rises to maintain a level of systemic pressure that is adequate for perfusion of the heart and brain at the expense of other tissues such as muscle, skin, and especially the gastrointestinal (GI) tract. Systemic vascular resistance is determined primarily by the luminal diameter of arterioles. The metabolic rates of the heart and brain are high, and their stores of energy substrate are low. These organs are critically dependent on a continuous supply of oxygen and nutrients, and neither tolerates severe ischemia for more than brief periods (minutes). Autoregulation (i.e., the maintenance of blood flow over a wide range of perfusion pressures) is critical in sustaining cerebral and coronary perfusion despite significant hypotension. However, when MAP drops to ≤60 mmHg, blood flow to these organs falls, and their function deteriorates.
Arteriolar vascular smooth muscle has both α- and β-adrenergic receptors. The α1 receptors mediate vasoconstriction, while the β2 receptors mediate vasodilation. Efferent sympathetic fibers release norepinephrine, which acts primarily on α1 receptors as one of the most fundamental compensatory responses to reduced perfusion pressure. Other constrictor substances that are increased in most forms of shock include angiotensin II, vasopressin, endothelin 1, and thromboxane A2. Both norepinephrine and epinephrine are released by the adrenal medulla, and the concentrations of these catecholamines in the bloodstream rise. Circulating vasodilators in shock include prostacyclin (prostaglandin [PG] I2), nitric oxide (NO), and, importantly, products of local metabolism such as adenosine that match flow to the tissue’s metabolic needs. The balance between these various vasoconstrictors and vasodilators influences the microcirculation and determines local perfusion.
Transport to cells depends on microcirculatory flow; capillary permeability; the diffusion of oxygen, carbon dioxide, nutrients, and products of metabolism through the interstitium; and the exchange of these products across cell membranes. Impairment of the microcirculation that is central to the pathophysiologic responses in the late stages of all forms of shock results in the derangement of cellular metabolism that is ultimately responsible for organ failure.
The endogenous response to mild or moderate hypovolemia is an attempt at restitution of intravascular volume through alterations in hydrostatic pressure and osmolarity. Constriction of arterioles leads to reductions in both the capillary hydrostatic pressure and the number of capillary beds perfused, thereby limiting the capillary surface area across which filtration occurs. When filtration is reduced while intravascular oncotic pressure remains constant or rises, there is net reabsorption of fluid into the vascular bed, in accord with Starling’s law of capillary interstitial liquid exchange. Metabolic changes (including hyperglycemia and elevations in the products of glycolysis, lipolysis, and proteolysis) raise extracellular osmolarity, leading to an osmotic gradient that increases interstitial and intravascular volume at the expense of intracellular volume.
Interstitial transport of nutrients is impaired in shock, leading to a decline in intracellular high-energy phosphate stores. Mitochondrial dysfunction and uncoupling of oxidative phosphorylation are the most likely causes for decreased amounts of adenosine triphosphate (ATP). As a consequence, there is an accumulation of hydrogen ions, lactate, reactive oxygen species, and other products of anaerobic metabolism. As shock progresses, these vasodilator metabolites override vasomotor tone, causing further hypotension and hypoperfusion. Dysfunction of cell membranes is thought to represent a common end-stage pathophysiologic pathway in the various forms of shock. Normal cellular transmembrane potential falls, and there is an associated increase in intracellular sodium and water, leading to cell swelling that interferes further with microvascular perfusion. In a preterminal event, homeostasis of calcium via membrane channels is lost with flooding of calcium into the cytosol and concomitant extracellular hypocalcemia. There is also evidence for a widespread but selective apoptotic (programmed cell death) loss of cells, contributing to organ and immune failure.
Hypovolemia, hypotension, and hypoxia are sensed by baroreceptors and chemoreceptors that contribute to an autonomic response that attempts to restore blood volume, maintain central perfusion, and mobilize metabolic substrates. Hypotension disinhibits the vasomotor center, resulting in increased adrenergic output and reduced vagal activity. Release of norepinephrine from adrenergic neurons induces significant peripheral and splanchnic vasoconstriction, a major contributor to the maintenance of central organ perfusion, while reduced vagal activity increases the heart rate and cardiac output. Loss of vagal activity is also recognized to upregulate the innate immune inflammatory response. The effects of circulating epinephrine released by the adrenal medulla in shock are largely metabolic, causing increased glycogenolysis and gluconeogenesis and reduced pancreatic insulin release. However, epinephrine also inhibits production and release of inflammatory mediators through stimulation of β-adrenergic receptors on innate immune cells.
Severe pain or other stresses cause the hypothalamic release of adrenocorticotropic hormone (ACTH). This stimulates cortisol secretion that contributes to decreased peripheral uptake of glucose and amino acids, enhances lipolysis, and increases gluconeogenesis. Increased pancreatic secretion of glucagon during stress accelerates hepatic gluconeogenesis and further elevates blood glucose concentration. These hormonal actions act synergistically to increase blood glucose for both selective tissue metabolism and the maintenance of blood volume. Many critically ill patients have recently been shown to exhibit low plasma cortisol levels and an impaired response to ACTH stimulation, which is linked to a decrease in survival. The importance of the cortisol response to stress is illustrated by the profound circulatory collapse that occurs in patients with adrenocortical insufficiency (Chap. 406).
Renin release is increased in response to adrenergic discharge and reduced perfusion of the juxtaglomerular apparatus in the kidney. Renin induces the formation of angiotensin I that is then converted to angiotensin II by the angiotensin converting enzyme; angiotensin II is an extremely potent vasoconstrictor and stimulator of aldosterone release by the adrenal cortex and of vasopressin by the posterior pituitary. Aldosterone contributes to the maintenance of intravascular volume by enhancing renal tubular reabsorption of sodium, resulting in the excretion of a low-volume, concentrated, sodium-free urine. Vasopressin has a direct action on vascular smooth muscle, contributing to vasoconstriction, and acts on the distal renal tubules to enhance water reabsorption.
Three variables—ventricular filling (preload), the resistance to ventricular ejection (afterload), and myocardial contractility—are paramount in controlling stroke volume (Chap. 265e). Cardiac output, the major determinant of tissue perfusion, is the product of stroke volume and heart rate. Hypovolemia leads to decreased ventricular preload that, in turn, reduces the stroke volume. An increase in heart rate is a useful but limited compensatory mechanism to maintain cardiac output. A shock-induced reduction in myocardial compliance is frequent, reducing ventricular end-diastolic volume and, hence, stroke volume at any given ventricular filling pressure. Restoration of intravascular volume may return stroke volume to normal but only at elevated filling pressures. Increased filling pressures stimulate release of brain natriuretic peptide (BNP) to secrete sodium and volume to relieve the pressure on the heart. Levels of BNP correlate with outcome following severe stress. In addition, sepsis, ischemia, myocardial infarction (MI), severe tissue trauma, hypothermia, general anesthesia, prolonged hypotension, and acidemia may all also impair myocardial contractility and reduce the stroke volume at any given ventricular end-diastolic volume. The resistance to ventricular ejection is significantly influenced by the systemic vascular resistance, which is elevated in most forms of shock. However, resistance is decreased in the early hyperdynamic stage of septic shock or neurogenic shock (Chap. 325), thereby initially allowing the cardiac output to be maintained or elevated.
The venous system contains nearly two-thirds of the total circulating blood volume, most in the small veins, and serves as a dynamic reservoir for autoinfusion of blood. Active venoconstriction as a consequence of α-adrenergic activity is an important compensatory mechanism for the maintenance of venous return and, therefore, of ventricular filling during shock. By contrast, venous dilation, as occurs in neurogenic shock, reduces ventricular filling and hence stroke volume and potentially cardiac output.
The response of the pulmonary vascular bed to shock parallels that of the systemic vascular bed, and the relative increase in pulmonary vascular resistance, particularly in septic shock, may exceed that of the systemic vascular resistance, leading to right heart failure. Shock-induced tachypnea reduces tidal volume and increases both dead space and minute ventilation. Relative hypoxia and the subsequent tachypnea induce a respiratory alkalosis. Recumbency and involuntary restriction of ventilation secondary to pain reduce functional residual capacity and may lead to atelectasis. Shock and, in particular, resuscitation-induced reactive oxygen species (oxidant radical) generation are recognized as major causes of acute lung injury and subsequent acute respiratory distress syndrome (ARDS; Chap. 322). These disorders are characterized by noncardiogenic pulmonary edema secondary to diffuse pulmonary capillary endothelial and alveolar epithelial injury, hypoxemia, and bilateral diffuse pulmonary infiltrates. Hypoxemia results from perfusion of underventilated and nonventilated alveoli. Loss of surfactant and lung volume in combination with increased interstitial and alveolar edema reduces lung compliance. The work of breathing and the oxygen requirements of respiratory muscles increase.
Acute kidney injury (Chap. 334), a serious complication of shock and hypoperfusion, occurs less frequently than heretofore because of early aggressive volume repletion. Acute tubular necrosis is now more frequently seen as a result of the interactions of shock, sepsis, the administration of nephrotoxic agents (such as aminoglycosides and angiographic contrast media), and rhabdomyolysis; the latter may be particularly severe in skeletal muscle trauma. The physiologic response of the kidney to hypoperfusion is to conserve salt and water. In addition to decreased renal blood flow, increased afferent arteriolar resistance accounts for diminished glomerular filtration rate (GFR) that, together with increased aldosterone and vasopressin, is responsible for reduced urine formation. Toxic injury causes necrosis of tubular epithelium and tubular obstruction by cellular debris with back leak of filtrate. The depletion of renal ATP stores that occurs with prolonged renal hypoperfusion contributes to subsequent impairment of renal function.
During shock, there is disruption of the normal cycles of carbohydrate, lipid, and protein metabolism. Through the citric acid cycle, alanine in conjunction with lactate, which is converted from pyruvate in the periphery in the presence of oxygen deprivation, enhances the hepatic production of glucose. With reduced availability of oxygen, the breakdown of glucose to pyruvate, and ultimately lactate, represents an inefficient cycling of substrate with minimal net energy production. An elevated plasma lactate/pyruvate ratio is preferable to lactate alone as a measure of anaerobic metabolism and reflects inadequate tissue perfusion. Decreased clearance of exogenous triglycerides coupled with increased hepatic lipogenesis causes a significant rise in serum triglyceride concentrations. There is increased protein catabolism as energy substrate, a negative nitrogen balance, and, if the process is prolonged, severe muscle wasting.
Activation of an extensive network of proinflammatory mediator pathways by the innate immune system plays a significant role in the progression of shock and contributes importantly to the development of multiple organ injury, multiple organ dysfunction (MOD), and MOF (Fig. 324-2). In those surviving the acute insult, there is a prolonged endogenous counterregulatory response to “turn off” or balance the excessive proinflammatory response. If balance is restored, the patient does well. If the response is excessive, adaptive immunity is suppressed and the patient is highly susceptible to secondary nosocomial infections, which may then drive the inflammatory response and lead to delayed MOF.
A schematic of the host immunoinflammatory response to shock. IFN, interferon; IL, interleukin; PG, prostaglandin; TGF, tumor growth factor; TNF, tumor necrosis factor.
Multiple humoral mediators are activated during shock and tissue injury. The complement cascade, activated through both the classic and alternate pathways, generates the anaphylatoxins C3a and C5a (Chap. 372e). Direct complement fixation to injured tissues can progress to the C5-C9 attack complex, causing further cell damage. Activation of the coagulation cascade (Chap. 141) causes microvascular thrombosis, with subsequent fibrinolysis leading to repeated episodes of ischemia and reperfusion. Components of the coagulation system (e.g., thrombin) are potent proinflammatory mediators that cause expression of adhesion molecules on endothelial cells and activation of neutrophils, leading to microvascular injury. Coagulation also activates the kallikrein-kininogen cascade, contributing to hypotension.
Eicosanoids are vasoactive and immunomodulatory products of arachidonic acid metabolism that include cyclooxygenase-derived prostaglandins (PGs) and thromboxane A2, as well as lipoxygenase-derived leukotrienes and lipoxins. Thromboxane A2 is a potent vasoconstrictor that contributes to the pulmonary hypertension and acute tubular necrosis of shock. PGI2 and PGE2 are potent vasodilators that enhance capillary permeability and edema formation. The cysteinyl leukotrienes LTC4 and LTD4 are pivotal mediators of the vascular sequelae of anaphylaxis, as well as of shock states resulting from sepsis or tissue injury. LTB4 is a potent neutrophil chemoattractant and secretagogue that stimulates the formation of reactive oxygen species. Platelet-activating factor, an ether-linked, arachidonyl-containing phospholipid mediator, causes pulmonary vasoconstriction, bronchoconstriction, systemic vasodilation, increased capillary permeability, and the priming of macrophages and neutrophils to produce enhanced levels of inflammatory mediators.
Tumor necrosis factor α (TNF-α), produced by activated macrophages, reproduces many components of the shock state, including hypotension, lactic acidosis, and respiratory failure. Interleukin 1β (IL-1β), originally defined as “endogenous pyrogen” and produced by tissue-fixed macrophages, is critical to the inflammatory response. Both are significantly elevated immediately following trauma and shock. IL-6, also produced predominantly by the macrophage, has a slightly delayed peak response but is the best single predictor of prolonged recovery and development of MOF following shock. Chemokines such as IL-8 are potent neutrophil chemoattractants and activators that upregulate adhesion molecules on the neutrophil to enhance aggregation, adherence, and damage to the vascular endothelium. While the endothelium normally produces low levels of NO, the inflammatory response stimulates the inducible isoform of NO synthase (iNOS), which is overexpressed and produces toxic nitroxyl- and oxygen-derived free radicals that contribute to the hyperdynamic cardiovascular response and tissue injury in sepsis.
Multiple inflammatory cells, including neutrophils, macrophages, and platelets, are major contributors to inflammation-induced injury. Margination of activated neutrophils in the microcirculation is a common pathologic finding in shock, causing secondary injury due to the release of toxic oxygen radicals, lipases (primarily PLA2), and proteases. Release of high levels of reactive oxygen intermediates/species (ROI/ROS) rapidly consumes endogenous essential antioxidants and generates diffuse oxygen radical damage. Newer efforts to control ischemia/reperfusion injury include treatment with carbon monoxide, hydrogen sulfide, or other agents to reduce oxidant stress. Tissue-fixed macrophages produce virtually all major mediators of the inflammatory response and orchestrate the progression and duration of the inflammatory response. A major source of activation of the monocyte/macrophage is through the highly conserved membrane toll-like receptors (TLRs) that recognize DAMPs, such as HMGB-1, and pathogen-associated molecular patterns (PAMPs), such as endotoxins released following tissue injury, and by pathogenic microbial organisms, respectively. TLRs also appear important in the chronic inflammation seen in Crohn’s disease, ulcerative colitis, and transplant rejection. The variability in individual responses is a genetic predisposition that, in part, is due to variants in genetic sequences affecting the function and production of various inflammatory mediators.
TREATMENT Shock MONITORING
Patients in shock require care in an intensive care unit (ICU). Careful and continuous assessment of the physiologic status is necessary. Arterial pressure through an indwelling line, pulse, and respiratory rate should be monitored continuously; a Foley catheter should be inserted to follow urine flow; and mental status should be assessed frequently. Sedated patients should be allowed to awaken (“drug holiday”) daily to assess their neurologic status and to shorten duration of ventilator support.
There is ongoing debate as to the indications for using the flow-directed pulmonary artery catheter (PAC; Swan-Ganz catheter) in the ICU. A recent Cochrane analysis showed that the use of a PAC did not alter mortality, length of stay, or cost for adult ICU patients. Most patients in the ICU can be safely managed without the use of a PAC. However, in shock with significant ongoing blood loss, fluid shifts, and underlying cardiac dysfunction, a PAC may be useful. The PAC is placed percutaneously via the subclavian or jugular vein through the central venous circulation and right heart into the pulmonary artery. There are ports both proximal in the right atrium and distal in the pulmonary artery to provide access for infusions and for cardiac output measurements. Right atrial and pulmonary artery pressures (PAPs) are measured, and the pulmonary capillary wedge pressure (PCWP) serves as an approximation of the left atrial pressure. Normal hemodynamic parameters and their derivation are summarized in Table 272-2 and Table 324-2.
Cardiac output is determined by the thermodilution technique, and high-resolution thermistors can also be used to determine right ventricular end-diastolic volume to monitor further the response of the right heart to fluid resuscitation. A PAC with an oximeter port offers the additional advantage of online monitoring of the mixed venous oxygen saturation, an important index of overall tissue perfusion. Systemic and pulmonary vascular resistances are calculated as the ratio of the pressure drop across these vascular beds to the cardiac output (Chap. 272). Determinations of oxygen content in arterial and venous blood, together with cardiac output and hemoglobin concentration, allow calculation of oxygen delivery, oxygen consumption, and oxygen-extraction ratio (Table 324-3). The hemodynamic patterns associated with the various forms of shock are shown in Table 324-4.
In resuscitation from shock, it is critical to restore tissue perfusion and optimize oxygen delivery, hemodynamics, and cardiac function rapidly. A reasonable goal of therapy is to achieve a normal mixed venous oxygen-saturation and arteriovenous oxygen-extraction ratio. To enhance oxygen delivery, red cell mass, arterial oxygen saturation, and cardiac output may be augmented singly or simultaneously. An increase in oxygen delivery not accompanied by an increase in oxygen consumption implies that oxygen availability is adequate and that oxygen consumption is not flow dependent. Conversely, an elevation of oxygen consumption with increased delivery implies that the oxygen supply was inadequate. However, cautious interpretation is required due to the link among increased oxygen delivery, cardiac work, and oxygen consumption. A reduction in systemic vascular resistance accompanying an increase in cardiac output indicates that compensatory vasoconstriction is reversing due to improved tissue perfusion. The determination of stepwise expansion of blood volume on cardiac performance allows identification of the optimum preload (Starling’s law). An algorithm for the resuscitation of the patient in shock is shown in Fig. 324-3.
TABLE 324-2Normal Hemodynamic Parameters ||Download (.pdf) TABLE 324-2 Normal Hemodynamic Parameters
|Parameter ||Calculation ||Normal Values |
|Cardiac output (CO) ||SV × HR ||4–8 L/min |
|Cardiac index (CI) ||CO/BSA ||2.6–4.2 (L/min)/m2 |
|Stroke volume (SV) ||CO/HR ||50–100 mL/beat |
|Systemic vascular resistance (SVR) ||([MAP – RAP]/CO) × 80 ||700–1600 dynes·s/cm5 |
|Pulmonary vascular resistance (PVR) ||([PAPm– PCWP]/CO) × 80 ||20–130 dynes·s/cm5 |
|Left ventricular stroke work (LVSW) ||SV(MAP – PCWP) × 0.0136 ||60–80 g-m/beat |
|Right ventricular stroke work (RVSW) ||SV(PAPm – RAP) ||10–15 g-m/beat |
TABLE 324-3Oxygen Transport Calculations ||Download (.pdf) TABLE 324-3 Oxygen Transport Calculations
|Parameter ||Calculation ||Normal Values |
|Oxygen-carrying capacity of hemoglobin || ||1.39 mL/g |
|Plasma O2 concentration || ||Po2 × 0.0031 |
|Arterial O2 concentration (Cao2) ||1.39 Sao2 + 0.0031 Pao2 ||20 vol% |
|Venous O2 concentration (Cvo2) ||1.39 Svo2 + 0.0031 Pvo2 ||15.5 vol% |
|Arteriovenous O2 difference (Cao2 – Cvo2) ||1.39 (Sao2 – Svo2) + 0.0031 (Pao2 – Pvo2) ||3.5 vol% |
|Oxygen delivery (Do2) ||Cao2 × CO (L/min) × 10 (dL/L) ||800–1600 mL/min |
| ||1.39 Sao2 × CO × 10 || |
|Oxygen uptake (Vo2) ||(Cao2 – Cvo2) × CO × 10 ||150–400 mL/min |
| ||1.39 (Sao2 – Svo2) × CO × 10 || |
|Oxygen delivery index (Do2I) ||Do2/BSA ||520–720 (mL/min)/m2 |
|Oxygen uptake index (Vo2I) ||Vo2/BSA ||115–165 (mL/min)/m2 |
|Oxygen extraction ratio (O2ER) ||[1 – (˙Vo2/˙Do2)] × 100 ||22–32% |
TABLE 324-4Physiologic Characteristics of the Various Forms of Shock ||Download (.pdf) TABLE 324-4 Physiologic Characteristics of the Various Forms of Shock
|Type of Shock ||CVP and PCWP ||Cardiac Output ||Systemic Vascular Resistance ||Venous O2 Saturation |
|Hypovolemic ||↓ ||↓ ||↑ ||↓ |
|Cardiogenic ||↑ ||↓ ||↑ ||↓ |
|Septic || || || || |
| Hyperdynamic ||↓↑ ||↑ ||↓ ||↑ |
| Hypodynamic ||↓↑ ||↓ ||↑ ||↓↑ |
|Traumatic ||↓ ||↓↑ ||↑↓ ||↓ |
|Neurogenic ||↓ ||↓ ||↓ ||↓ |
|Hypoadrenal ||↓ ||↓ ||=↓ ||↓ |
An algorithm for the resuscitation of the patient in shock. Monitor Svo2, SVRI, and RVEDVI as additional markers of correction for perfusion and hypovolemia. Consider age-adjusted CI. CI, cardiac index in (L/min) per m2; CVP, central venous pressure; ECHO, echocardiogram; Hct, hematocrit; HR, heart rate; PAC, pulmonary artery catheter; PCWP, pulmonary capillary wedge pressure in mmHg; RVEDVI, right ventricular end-diastolic volume index; SBP, systolic blood pressure; Svo2, saturation of hemoglobin with O2 in venous blood; SVRI, systemic vascular resistance index; VS, vital signs; W/U, workup.